While some trends in antimicrobial resistance rates are universal,
others appear to be unique for specific regions. In Taiwan, the
strikingly high prevalence of resistance to macrolides and streptogramin
in clinical isolates of gram-positive bacteria correlates with the
widespread use of these agents in the medical and farming communities,
respectively. The relatively low rate of enterococci that are resistant
to glycopeptide does not parallel the high use of glycopeptides and
extended-spectrum beta-lactams in hospitals. The evolving problem of
extended-spectrum beta-lactamase-producing Escherichia coil and
Klebsiella pneumoniae isolates is substantial, and some unique enzymes
have been found. Recently, some gram-negative bacteria (e.g.,
Pseudomonas aeruginosa and Acinetobacter baumannii) that are resistant
to all available antimicrobial agents including carbapenems have
emerged.

**********

Antimicrobial resistance has become a major health problem
worldwide, affecting every country to some degree. It is an inevitable
consequence of the inappropriate use of antibiotics in humans and
animals. In Europe and North America, methicillin-resistant
Staphylococcus aureus (MRSA), penicillin-nonsusceptible Streptococcus
pneumoniae (PNSSP), vancomycin-resistant enterococci (VRE), and
extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae
have emerged and spread into communities and hospitals. In Taiwan, the
widespread use of antimicrobial agents in primary care clinics and
animal husbandry has allowed the rapid emergence of resistant bacteria.
During the last 2 decades, many antimicrobial agents--such as
extended-spectrum cephalosporins, carbapenems, fluoroquinolones, and
aminoglycosides--have been introduced and empirically used as first-line
drugs to treat these resistant bacteria (1,2). This has further
accelerated the development and dissemination of drug-resistant
bacteria. Previous studies in Taiwan have clearly demonstrated the
remarkably high prevalence of some critically resistant bacteria, such
as MRSA, PNSSP, and macrolide-resistant streptococci (1,2). In addition,
several multidrug-resistant bacteria, including ones resistant to
carbapenems and fluoroquinolones and pan-drug-resistant gram-negative
bacilli, have been isolated from different hospitals (3-6).

Approval of Antibiotics

Table 1 shows the years that selected antibiotics were approved in
Taiwan. These antibiotics are now widely used to treat various
infections, including community-acquired and nosocomial infections.
Until now, two gylcopeptides (vancomycin and teicoplanin), two
carbapenems (imipenem and meropenem), four macrolides (erythromycin,
roxithromycin, clarithromycin, and azithromycin), and six quinolones
(nalidixic acid, norfloxacin, ofloxacin, lomefloxacin, ciprofloxacin,
and levofloxacin) have been available for clinical use in Taiwan. Most
of these drugs were also readily available at drugstores without
prescription before 1995.

Drug-Resistant Bacteria

The following drug-resistance data were collected from a nationwide
resistance survey (Surveillance from Multicenter Antimicrobial
Resistance in Taiwan) of clinical isolates (including those recovered
from hospitals and outpatients) from 12 major hospitals as well as
isolates causing nosocomial infections from National Taiwan University
Hospital (NTUH) in 2000 in Taiwan. These hospitals are located in
different parts of the country. The number of beds in these hospitals
ranged from 800 to 3,200. All these data were derived by using the
disk-diffusion method (7).

Some dilution antimicrobial susceptibility and epidemiology
studies, including [greater than or equal to] 100 strains published in
English-language journals from January 1995 through 2001, were also
included. Rather than provide a comprehensive review of all resistance
problems in Taiwan, our aim was to point out some of the more critical
resistance problems threatening the treatment of infections caused by
Staphylococcus species, S. pyogenes, Streptococcus pneumoniae,
Enterococcus species, and Mycobacterium tuberculosis among the
gram-positive pathogens, and Haemophilus influenzae, Escherichia coli,
Klebsiella pneumoniae, Enterobacter species, Salmonella species,
Campylobacter species, Pseudomonas aeruginosa, and Acinetobacter
baumannii among the gram-negative pathogens. Resistance rates included
in this review reflect both intermediate and fully resistant
populations. Table 2 summarizes the prevalence of antimicrobial
resistance among clinical isolates (12 hospitals, including NTUH) and
nosocomial isolates (from NTUH only) of some selected bacterial species.
The ranges in numbers of clinical isolates of select bacteria (Table 2)
recovered from these hospitals were as follows: Staphylococcus aureus,
1,889 to 7,516 isolates; beta-hemolytic streptococci, 335 to 1,102; S.
pneumoniae, 138 to 461; enterococci, 509 to 3,676; H. influenzae, 427 to
602; E. coli, 1,734 to 9,553; K. pneumoniae, 950 to 3,226; E. cloacae,
427 to 1,426; nontyphoid Salmonella, 94 to 626; P aeruginosa, 1,741 to
4,896; and A. baumannii, 896 to 2,434.

Gram-Positive Bacteria

MRSA

MRSA was first documented in Taiwan in the early 1980s (8). Since
then, there has been a remarkable increase in prevalence of MRSA in
nosocomial infections (from 26.7% in 1990 to 75% to 84% in 1998-2000)
(9). Several dominant clones have been documented in hospitals (9). The
prevalence of MRSA in community-acquired infections remains unclear,
although the incidence of MRSA among patients of outpatient departments
is estimated to be 40% (1). Data from a survey of >5,000 clinical
isolates of S. aureus at the NTUH from January 1999 to June 2001 using
brain-heart-infusion agar plus 4 mg/L of vancomycin showed results
negative for vancomycin-intermediate or -resistant strains.

PNSSP and Multidrug-Resistant Streptococcus pneumoniae (MDRSP)

The overall prevalence of clinical isolates of PNSSP in 1999-2000
was 60% to 80%, including 20% to 30% penicillin-intermediate and 40% to
50% penicillin-resistant strains (10-16). This prevalence of PNSSP was
slightly lower than that in Korea and higher than that in most other
geographic areas (15,16). All PNSSP were resistant to multiple
antibiotics (13,16). This resistance was higher among nasopharyngeal isolates from children (12). Approximately 60% of the PNSSP isolates
were also not susceptible to extended-spectrum cephalosporins and
carbapenems (13). Most of these PNSSP belong to serotypes 23F, 19F, 6B,
and 14 (13,15). Wide dissemination of multiple high-level penicillin-,
extended-spectrum cephalosporin-, and macrolide-resistant clones as well
as the Spain 23F clone contributes to the high rates of resistance to
these drugs in clinical isolates of S. pneumoniae (14,17). Only one
clinical isolate was reported to be resistant to fluoroquinolones (18).

VRE and Glycopeptide-Resistant Staphylococci

The first clinical isolate of Van-A-phenotype VRE (E. faecalis) was
found in 1995 (19). Since then, isolation of VRE remains rare and
accounts for <3% of all clinical isolates of enterococci (20,21). The
proportion of Enterococcus hospital isolates resistant to vancomycin in
Taiwan is low compared with those in North America and Europe (22), a
finding that needs further investigation. However, an increase in VRE
isolation associated with the continuous widespread use of glycopeptides
in a Taiwanese university hospital was observed (23). Furthermore,
interhospital and nosocomial spread of some VRE clones, particularly one
vanB2 E. faecium clone, or long-term persistence of multiple clones in
hospitalized patients still exists (21,24). Although avoparcin has been
approved for veterinary use since 1977, this agent has been banned in
the farming industry since 2000 (24). Glycopeptide resistance has been
found in some isolates of coagulase-negative staphylococci, particularly
in S. simulans and S. warneri (25).

Macrolide-Resistant Streptococci

Under the increasing and highly selective pressure of macrolide
usage in Taiwan, the prevalence of macrolide resistance and distribution
of M-phenotype (reef gene-positive) among macrolide-resistant isolates
vary among different streptococcal species (Figure) (26-31). More than
90% of the S. pneumoniae isolates were resistant to macrolides, and
approximately two thirds exhibited high-level resistance (ML[S.sub.B]
phenotype-erm gene-positive) (29). However, macrolide resistance
accounted for 50% to 60% of all clinical isolates of S. pyogenes, and a
stepwise increase of proportion of M phenotype was clearly demonstrated
(29).

[FIGURE OMITTED]

Streptogramin-Resistant Gram-Positive Cocci

Quinupristin-dalfopristin is not available for clinical use in
Taiwan; nevertheless, the incidence of resistance to this agent was high
(51%) in vancomycin-resistant E. faecium (25). Three resistant E.
faecium isolates were recovered from animal sources (pigs) in Taiwan.
Restricted use of virginiamycin, which has been widely used in animal
feed for >20 years in this country, might be required to alleviate
quinupristin-dalfopristin resistance among bacteria from human sources
(25).

Multidrug-Resistant Mycobacterium tuberculosis (MDRTB)

The prevalence of pulmonary tuberculosis (TB) in adults was 0.65%
in 1993, and the associated death rate was 6.93 per 100,000 in 1998
(32). The overall incidence of isoniazid-resistant M. tuberculosis was
31.5%. The incidence of primary resistance (isolates from patients with
newly diagnosed TB who had no prior history of anti-TB therapy or from
patients whose anti-TB therapy was begun <2 weeks) was 12.0%; the
incidence of acquired resistance (isolates from patients who had a prior
history of anti-TB medication) was 63.0%. The overall incidence of MDRTB
was 17.3% (primary resistance 1.6%; acquired resistance 46%) (33). An
aggressive intervention program, such as expanded use of directly
observed therapy, short course, is ongoing to improve the cure rate of
TB and to decrease the resistance rate.

Gram-Negative Bacilli

H. influenzae and Moraxella catarrhalis

The annual incidence of invasive H. influenzae type b disease in
children <5 years old was 1.6 to 1.9 per 100,000 population per year
before the introduction of conjugated Hib vaccine in 1995 (34).
Beta-lactamase production was found in 50% to 60% of H, influenzae and
in >95% of M. catarrhalis. BRO-1 isoform accounts for 88% of all
beta-lactamase producers of M. catarrhalis (16,35,36). Among
amoxicillin-resistant H. influenzae isolates, beta-lactamase
nonproducers were rare (<2%) (16). A continuing upsurge of H.
influenzae isolates resistant to macrolide (30%) and to
trimethoprim-sulfamethoxazole (50%) during the last decade has become
evident (16,35).

Enterobacteriaceae

The proportion of isolates of K. pneumoniae exhibiting the ESBL
phenotype has increased progressively from 3.4% in 1993 to 10.3% in 1997
in NTUH (37). Approximately one fifth of the ESBL-producing K.
pneumoniae were also resistant to ciprofloxacin (37). From 1998 through
2000, several reports from different hospitals showed that ESBL
production accounts for 8% to 30% of clinical isolates of K. pneumoniae.
Those producing SHV-5 and SHV-12 predominated. In addition, four novel
beta-lactamases (CMY-8, SHV-25, SHV-26, and IMP-8) were identified in
2000 in Taiwan (38-42). Among the ESBL-producing E. coli isolates, which
accounted for 1.6% to 6.7%, strains having CTX-M-3 and CMY-M-2 were
disseminated in Taiwan (39,43). In Taiwan, the previous belief that
characteristically susceptible strains (uniformly susceptible to
cephalosporins) of K. pneumoniae caused primary liver abscess, an
endemic disease entity in patients with diabetes mellitus, has now been
disproved because two cephalosporin-resistant K. pneumoniae strains
causing primary liver abscess have been found (44-46).

More than 40% of clinical isolates of nontyphoid Salmonella species
were resistant to multiple antibiotics (ampicillin, chloramphenicol, and
trimethoprim-sulfamethoxazole). Resistance to cefotaxime and
fluoroquinolones was estimated to be low (1% to 3%) (47).

P. aeruginosa, A. baumannii, and Other Bacteria

P. aeruginosa, A. baumannii, and other nonfermentative
gram-negative bacilli are usually resistant to various antimicrobial
agents. A high proportion of clinical isolates, particularly those
recovered from patients in intensive-care units, that are resistant to
some last-line agents (ceftazidime, amikacin, ciprofloxacin, and
carbapenems) have now been found in Taiwan (3-6,48,49). A small outbreak
of infections (three patients) caused by a pan-drug-resistant P
aeruginosa (sero-group O:4) clone in an intensive-care bum unit from
April 1997 to May 1997 has been identified (3) This clone had been
isolated from a patient on the same unit 5 months before the outbreak
(3). Among P. aeruginosa isolates with reduced susceptibilities to
imipenem, VIM-2 and VIM-3 are the predominant metallo-beta-lactamases
(50). Furthermore, clonal dissemination of VIM-3-producing P aeruginosa
has been found among hospitals in Taiwan (50). Strains of ceftazidime-
and ciprofloxacin-resistant A. baumannii causing severe
community-acquired pneumonia have emerged (49). Infections caused by
Chryseobacterium indologenes, a multidrug-resistant nosocomial pathogen,
appear to be another emerging problem in Taiwan (5). Isolates of the
Chryseobacterium genus have remarkable discrepancies of susceptibility
results by the disk-diffusion and dilution method. Vancomycin is not
recommended as a drug of choice for treating C. meningosepticum
meningitis or other infections caused by Chryseobacterium species
because these isolates are highly resistant to vancomycin when the
standard agar dilution method is used (4).

Several multidrug-resistant (extended-spectrum cephalosporins,
ciprofloxacin, or carbapenem resistance) Aeromonas species have been
reported (51,52). A derepressed mutant of A. hydrophila, which
overexpresses beta-lactamases and shows resistance to extended-spectrum
cephalosporins, is used if treatment with cefotaxime for Aeromonas
bacteremia fails (52). High prevalence of ciprofloxacin resistance for
human isolates of Campylobacter jejuni (52%) and C. coli (75%) may be
attributable to the widespread use of quinolones in poultry in Taiwan
(53,54).

Strategy for Resistance Control in the 21st Century

By the end of the 20th century, many measures to control resistance
problems had been instituted in Taiwan. Antibiotics had been removed
from the list of available nonprescription drugs at drugstores.
Antibiotic interventions had been implemented in many hospitals,
particularly in intensive-care units, to alleviate the high prevalence
of resistance among nosocomial pathogens. In 2000, the Council of
Agriculture in Taiwan prohibited the use of several antimicrobial agents
(such as avoparcin, kanamycin, kitasamycin, lasalocid, spiramycin,
salinomycin, and streptomycin), which had been widely used as growth
promoters or prophylactic agents in animal husbandry in Taiwan during
the past 2 to 3 decades, because they may select for critical forms of
resistance in human pathogens in food-producing animals (54). Further
research is ongoing to reduce the risk for increasing resistance in
human pathogens caused by antibiotic use in animal husbandry. In the new
millennium, the Center for Disease Control, Department of Health, in
Taiwan, has made control of antimicrobial resistance a major goal. The
two main tasks are to restrict use of antibiotics for trivial upper
respiratory tract infections and to avoid inappropriate use of
antibiotics for surgical prophylaxis.

* National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; t and Taipei Veterans General
Hospital and National Yang-Ming University, Taipei, Taiwan. Most of
these drugs were also readily available at drugstores without
prescription before 1995.

Dr. Hsueh is assistant professor in the Departments of Laboratory
Medicine and Internal Medicine at National Taiwan University College of
Medicine in Taipei, Taiwan. His research interests include the
epidemiology of emerging and nosocomial infections and mechanisms of
antimicrobial drug resistance. He is actively involved in developing a
national research program for antimicrobial drug resistance
(Surveillance for Multicenter Antimicrobial Resistance in Taiwan-SMART).

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